Article
Reference
Prevalence of metastatic lateral lymph nodes in asian patients with lateral lymph node dissection for rectal cancer: a meta-analysis
CHRISTOU, Niki, et al.
Abstract
Rectal cancers occupy the eighth position worldwide for new cases and deaths for both men and women. These cancers have a high tendency to form metastases in the mesorectum but also in the lateral lymph nodes. The therapeutic approach for the involved lateral lymph nodes remains controversial.
CHRISTOU, Niki, et al . Prevalence of metastatic lateral lymph nodes in asian patients with lateral lymph node dissection for rectal cancer: a meta-analysis. World Journal of Surgery , 2021, vol. 45, no. 5, p. 1537-1547
DOI : 10.1007/s00268-021-05956-1 PMID : 33543333
Available at:
http://archive-ouverte.unige.ch/unige:154574
Disclaimer: layout of this document may differ from the published version.
S C I E N T I F I C R E V I E W
Prevalence of Metastatic Lateral Lymph Nodes in Asian Patients with Lateral Lymph Node Dissection for Rectal Cancer: A Meta- analysis
Niki Christou1,2 •Jeremy Meyer2,3•Christophe Combescure4• Alexandre Balaphas2,3• Joan Robert-Yap2,3•Nicolas C. Buchs2,3•Fre´de´ric Ris2,3
Accepted: 5 January 2021 ÓThe Author(s) 2021
Abstract
Importance Rectal cancers occupy the eighth position worldwide for new cases and deaths for both men and women.
These cancers have a high tendency to form metastases in the mesorectum but also in the lateral lymph nodes. The therapeutic approach for the involved lateral lymph nodes remains controversial.
Objective We performed a systematic review and meta-analysis to assess the prevalence of metastatic lateral lymph nodes in patients with lateral lymph node dissection (LLND) for rectal cancer, which seems to be a fundamental and necessary criterion to discuss any possible indications for LLND.
Methods Data sources–study selection–data extraction and synthesis–main outcome and measures. We searched MEDLINE, EMBASE and COCHRANE from November 1, 2018, to November 19, 2018, for studies reporting the presence of metastatic lateral lymph nodes (iliac, obturator and middle sacral nodes) among patients undergoing rectal surgery with LLND. Pooled prevalence values were obtained by random effects models, and the robustness was tested by leave-one-out sensitivity analyses. Heterogeneity was assessed using the Q-test, quantified based on the I2 value and explored by subgroup analyses.
Results Our final analysis included 31 studies from Asian countries, comprising 7599 patients. The pooled preva- lence of metastatic lateral lymph nodes was 17.3% (95% CI: 14.6–20.5). The inter-study variability (heterogeneity) was high (I2= 89%). The pooled prevalence was, however, robust and varied between 16.6% and 17.9% according to leave-one-out sensitivity analysis. The pooled prevalence of metastatic lymph nodes was not significantly different when pooling only studies including patients who received neoadjuvant treatment or those without neoadjuvant treatment (p = 0.44). Meta-regression showed that the pooled prevalence was associated with the sample size of studies (p\0.05), as the prevalence decreased when the sample size increased.
Conclusion The pooled prevalence of metastatic lateral lymph nodes was 17.3% among patients who underwent rectal surgery with LLND in Asian countries. Further studies are necessary to determine whether this finding could impact the therapeutic strategy (total mesorectal excision with LLND versus total mesorectal excision with neoadjuvant radiochemotherapy).
Supplementary Information The online version contains supplementary material available at(https://doi.org/10.1007/s00268- 021-05956-1)
& Niki Christou
1 Digestive Surgery Department, University Hospital of Limoges, 2 Avenue Martin Luther King, 87042 Limoges, France
2 Division of Digestive Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil, 41211 Geneva 14, Switzerland
3 Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
https://doi.org/10.1007/s00268-021-05956-1
Abbreviations
LLND Lateral lymph node dissection RCT Randomized controlled trial
Introduction
Rectal cancer metastasizes to the perirectal lymph nodes contained within the mesorectum and along the iliac arteries [1]. Assessment of lymph node involvement is a strong predictor of recurrence-free survival and overall survival in patients with rectal cancer [2]. Currently, total mesorectal excision constitutes the gold standard for removing perirectal lymph nodes [3]. However, the thera- peutic strategy regarding lymph nodes, notably those located along the iliac arteries, may include neoadjuvant radiochemotherapy, as performed in Western countries [3], or lateral lymph node dissection (LLND), as performed in Japan when the lower border of the tumour is located under the reflection of the peritoneum and when it has passed the muscularis propria[4].
However, to date, only two randomized controlled trials (RCTs) [5, 6] have compared the outcomes of the two therapeutic strategies in terms of survival, looking at local and distant recurrences and complications. Furthermore, the choice of the best strategy, either LLND or radiochemotherapy or the combination of the two treat- ments, is difficult to identify, as the prevalence of meta- static lateral lymph nodes in patients with rectal cancer is poorly documented. Indeed, before comparing two thera- peutic strategies and their outcomes, it is necessary and more relevant to know if it is legitimate to propose them as a treatment; in other words, if they would even correctly target metastatic lateral lymph nodes (LLNs).
Therefore, our objective was to perform a systematic review and meta-analysis reporting on the prevalence of metastatic lateral lymph nodes in patients with rectal can- cer with the hypothesis that this meta-analysis will eluci- date the best therapeutic strategy in the current absence of reliable assessment of tumour aggressiveness.
Materials and methods
The present methodology is in accordance with the Pre- ferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) checklist (Table S1).
Literature search and study selection
A literature search was conducted in MEDLINE, EMBASE and COCHRANE from inception (DATE??) until November 19, 2018. Keyword combinations are reported in Table S2. Additional records were identified by manually searching the reference lists of the included publications.
To be included, studies had to be written in English or French and to report the prevalence of metastatic lateral lymph nodes among patients with rectal cancer who underwent surgery with LLND. LLND was defined by the dissection of nodes included in areas such as the common iliac (IC), internal iliac (II), external iliac (EI), obturator (O), middle sacral (MS) and aorta bifurcation (Ao).
We excluded case series, conference abstracts, letters to the editor and secondary analyses of previously published papers.
Data extraction
Two independent reviewers (NC and JM) independently selected articles for inclusion and extracted the data according to a pre-established data collection form. Dis- crepancies were resolved by reaching a consensus with the senior authors (NCB and FR). The following data were extracted: first author; publication year; country where the study took place; study period, after and before 2010 due to modifications of the Japanese Guidelines for LLND; study design; number of patients who underwent LLND, pro- phylactic: dissection and removal of nodes that seem invaded (enlarged) based on pre- and peri-operative examinations, versus therapeutic/curative: removal of all nodes in the ‘‘lateral lymph area’’; sex; number of patients with metastatic lateral lymph nodes; number of patients who underwent pre-operative radio- and/or chemotherapy;
type of neoadjuvant treatment in those patients; and oncological stages of included patients.
Statistical analysis
Models with random effects (DerSimonian and Laird’s approach [7]) were used to combine the prevalence of metastatic lateral lymph nodes across the studies. A logit transformation was applied to prevalence before statistical pooling, and the pooled logit of prevalence was then transformed back. Heterogeneity was assessed by using the I2 statistic, and a leave-one-out sensitivity analysis was conducted to check the robustness of the pooled preva- lence. Potential sources of heterogeneity were investigated by comparing the pooled prevalence between subgroups of studies. A sensitivity analysis was also conducted exclud- ing stage 4 patients from the denominator and from the numerator of the prevalence because stage 4 patients were
4 Division of Clinical Epidemiology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland
assumed to have metastatic lateral lymph nodes (model with random effects). In addition, a meta-regression anal- ysis was conducted to assess the relationship between the sample size of studies and the prevalence with the restricted maximum likelihood method. [8] All analyses were performed with the Meta and Metafor packages for R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Literature search and study characteristics
Two hundred and sixty-five publications were identified in MEDLINE, EMBASE and COCHRANE. Three publica- tions were identified from other sources. Fifteen duplicates were removed. Of the 250 publications that were identified as eligible, 155 were excluded after title/abstract screening, and 64 were excluded after full-text screening (44 publi- cations did not report the number of patients with meta- static lateral lymph nodes and 20 publications did not distinguish patients with metastatic lateral lymph nodes from those with metastatic lymph nodes from other areas).
Ultimately, 31 publications [5,6,9–37] were included in the quantitative synthesis, all coming from Japan except one from China (Fig.1, Table1).
Among the included publications, 28 were retrospective cohort studies [9–35, 37], one was a prospective cohort study [36] and two were RCTs [5,6]. Thirty studies were performed in Japan [5,6, 9–33, 35–37] and one in China [34]. Eleven studies only included patients with TNM cancer stages 2 and 3 [5,9–13,15,31,32,35,38]. In 24 studies [5, 6, 9–11, 15, 17–28, 31–35, 37], systematic LLND was performed in all included patients, whereas in six studies [12–14,16,29,30,36], LLND was performed only in patients with enlarged lateral lymph nodes on pre- operative imaging, which distinguished these patients from others who had confirmation by histopathological results.
In one study, the type of LLND was not described [28]. In two studies, patients underwent systematic bilateral dis- section [22, 32]; in 27 studies, uni- or bilateral dissection was defined according to clinical and/or imaging findings [6,12–21,23, 25,26,28–31,37–39] and in four studies, lateralization of dissection was not documented [24,34–36]. Nine studies included patients who received neoadjuvant treatment [6, 11, 13–17, 30,31]. Indications for neoadjuvant treatment were not documented in four studies [11,15–17] and depended on tumour stage in five studies [13, 14, 16, 30, 31]. The characteristics of the included studies are reported in Tables2,3, S3, S4. It is worth noting that the study of Yano et al.has been clas- sified above as a study with ‘‘curative LLND’’ because pre-
imaging with enlarged nodes was considered the main decision-making criterion for LLND. However, in fact, after the flow chart analysis, dissection was also performed in a systematic way (Table S4). Thus, for statistical anal- ysis, we classified it as a ‘‘prophylactic study’’.
Prevalence of metastatic lateral lymph nodes
We obtained a pooled prevalence of metastatic lateral lymph nodes of 17.3% (95% CI: 14.6–20.5) (31 studies, 7599 patients) (Fig.2). The inter-study variability (heterogeneity) was noteworthy, with I2= 89%. In other words, the variation in study outcome (prevalence) between studies was high. Furthermore, the prediction interval was 6.5 to 38.6%. This means that if a new study is conducted, the assessed prevalence is likely, with a prob- ability of 95%, to fall between 6.5 and 38.6%. However, the pooled prevalence was robust according to leave-one- out sensitivity analysis. The pooled prevalence varied from 16.6% (14.0 to 19.5%), when the study by Yano et al.[36]
was omitted, to 17.9% (15.1 to 21.1%), when the study by Min et al.[16] was omitted (Fig. S1). The heterogeneity, however, remained stable, as the I2 statistic for hetero- geneity varied from 85%, when the study by Sato et al.[18]
was omitted, to 89.1%, when one of the following studies was omitted [6,10,13,15,21,23,25,26,32,34,35].
To determine whether neoadjuvant treatment could alter the prevalence of metastatic lateral lymph nodes, we per- formed subgroup analyses by separately pooling studies reporting patients who received neoadjuvant treatment from others (Fig. S2). The difference in pooled prevalence of metastatic lateral lymph nodes between studies with versuswithout neoadjuvant treatment was 16.9% (95% CI:
14.1–20.2), but the inter-study variability (heterogeneity) was high important, with I2= 88%.
Then, we explored whether the heterogeneity could be explained by changes in the therapeutic strategies across the years. The pooled prevalence of metastatic lateral lymph nodes between studies published before and after 2010 was 17.3% (95% CI: 14.6–20.4), but the inter-study variability (heterogeneity) was noteworthy, with I2= 89%
(Fig. S3).
Furthermore, we excluded patients with TNM stage IV (in six studies). After exclusion of these patients, the pooled prevalence of metastatic lateral lymph nodes was 15.8% (95% CI 13.1 to 18.9) (Fig. S4).
Then, we separately pooled studies according to the type of LLND performed (systematic versus curative). The difference in the pooled prevalence of metastatic lateral lymph nodes between studies with systematic or curative dissection was not statistically significant (p = 0.7111) (Fig. S5).
However, the pooled prevalence of metastatic lateral lymph nodes appeared to be associated with the sample size of studies (p = 0.005): the prevalence decreased when the sample size increased (Fig. S6). Meta-regression showed that, on average, a study with a sample size that was 10 times larger than that of some other study had an estimated odds ratio for prevalence that was reduced by approximately 50% (Fig. S7).
Discussion
We performed a systematic review and meta-analysis estimating the prevalence of metastatic lateral lymph nodes in patients with rectal cancer. By pooling 31 studies of Asian origin (30 from Japan and one from China) totalling 7599 patients, we found a prevalence of metastatic lateral lymph nodes of 17.3%, thereby underlining the importance of further examination of the treatment of these node areas to avoid cancer recurrence.
Six studies included patients with TNM stage IV rectal cancer. According to the most recent Japanese guidelines,
metastatic disease is not the most important stage to indi- cate LLND [4]. However, within this stage, some patients may present both primary tumour and resectable distant metastases, thus proceeding to the possibility of undergo- ing LLND. As a result, to understand the prevalence of metastatic lymph nodes within the most common indica- tions, we excluded patients with TNM stage IV disease by considering them to have metastatic lateral lymph nodes.
After exclusion, the pooled prevalence of metastatic lateral lymph nodes remained stable (15.8%).
In the present systematic review and meta-analysis, we were not able to show any improvement in neoadjuvant treatment in terms of lateral lymph node metastasis.
However, it should be noted that the power of this sub- group analysis might be insufficient. Additionally, Asian protocols differed from Western protocols, and only a small proportion of patients among studies with neoadju- vant treatment benefited from that modality. Therefore, it is not possible to draw any conclusions about the efficacy of neoadjuvant treatment in terms of the prevalence of metastatic lateral lymph nodes based on our results.
Despite this, it is worth noting that neoadjuvant treatments Fig. 1 Flow chart showing the
selection of publications for quantitative review. Forest plot of the prevalence of metastatic lateral lymph nodes in patients who underwent lateral lymph node dissection. Each horizontal bar summarizes a study. The bars represent 95% confidence intervals. The grey squares represent each of the studies’
weights in the meta-analysis.
The diamond in the lower part of the graph depicts the pooled estimate along with 95%
confidence intervals.
Events = number of patients with metastatic lateral lymph nodes, total = number of patients who underwent lateral lymph node dissection for rectal cancer
between the studies were quite similar using 5-fluorouracil, oxaliplatin and irinotecan (Table S3).
Some centres performed systematic LLND, whereas others performed LLND in patients with enlarged lateral lymph nodes diagnosed by pre-operative imaging. We pooled these studies separately and found no difference in terms of metastatic lateral lymph nodes. After 2010, as Japanese guidelines changed and recommended limiting LLND for all cT3-T4 tumours with a lower edge below the peritoneal reflection, we reported a subgroup analysis of the pooled prevalence of metastatic LLN according to the publication date. Due to the high heterogeneity, we cannot interpret this result as significant.
Furthermore, we note that meta-regression showed that the pooled prevalence of metastatic lymph nodes was
associated with the sample size of studies, as the preva- lence of metastatic lymph nodes decreased when the sample size increased. We think that this might be explained by more selective indications for LLND in studies including fewer patients with LLND. Thus, even if the number of studies between curative and systematic LLND intention was not the same, the tendency of the sample size of studies with curative LLND was lower. This indirectly shows that smaller studies were more likely to have a selected population. As a consequence, studies with larger sample sizes (in other words, studies with prophy- lactic LLND) were more likely to represent the ‘‘real’’
proportion of patients with rectal cancer with LLN metastasis.
Table 1 Characteristics of included studies
Author Year Cohort dates Design Mono-/multicentric Country
Fujita et al 2012 2010–2003 RCT Multicentric Japan
Hara et al 2007 1987–1999 Retrospective cohort Monocentric Japan
Ishibe et al 2016 2008–2012 Retrospective cohort Monocentric Japan
Kanemitsu et al 2017 1975–2009 Retrospective cohort Multicentric Japan
Ishida et al 2012 1997–2011 Retrospective cohort Monocentric Japan
Kagawa et al 2015 2012–2013 Retrospective cohort Monocentric Japan
Masaki et al 2010 2000–2009 RCT Monocentric Japan
Matsuoka et al 2007 1997–2005 Retrospective cohort Monocentric Japan
Miyake et al 2017 2014–206 Retrospective cohort Monocentric Japan
Min et al 2009 1996–2006 Retrospective cohort Monocentric Japan
Sato et al 2011 2005–2007 Prospective cohort Monocentric Japan
Sato et al 2011 1990–2005 Retrospective cohort Monocentric Japan
Shimoyama et al 2003 1981–1994 Retrospective cohort Monocentric Japan
Yokoyama et al 2014 2000–2008 Retrospective cohort Monocentric Japan
Komori et al 2013 1979–2001 Retrospective cohort Monocentric Japan
Masaki et al 2008 2000–2007 Retrospective cohort Monocentric Japan
Wu et al 2007 ns Retrospective cohort Monocentric Japan
Ueno et al 2007 1985–2000 Retrospective cohort Monocentric Japan
Steup et al 2002 1974–1990 Retrospective cohort Monocentric Japan
Mori et al 1998 1975–1996 Retrospective cohort Monocentric Japan
Tan et al 2010 1980–2008 Retrospective cohort Monocentric Japan
Nagasaki et al 2017 1985–2012 Retrospective cohort Monocentric Japan
Yamaoka et al 2017 2013–2015 Retrospective cohort Monocentric Japan
Numata et al 2017 2002–2013 Retrospective cohort Monocentric Japan
Yamaguchi et al 2016 2010–2014 Retrospective cohort Monocentric Japan
Yu et al 2011 2006–2007 Retrospective cohort Monocentric China
Kobayashi et al 2009 1991–1998 Retrospective cohort Multicentric Japan
Yano et al 2007 1995–2013 Prospective cohort Monocentric Japan
Kinugasa et al 2013 1975–2004 Retrospective cohort Monocentric Japan
Ueno et al 2005 1985–1999 Retrospective cohort Monocentric Japan
Hida et al 1997 1979–1988 Retrospective cohort Monocentric Japan
Table2Demographicsofincludedstudies AuthorsPatients, nWomen,n (%)Men,n(%)Age (median)T1,n(%)T2,n(%)T3,n(%)T4,n(%)Stage1, n(%)Stage2, n(%)Stage3, n(%)Stage4, n(%) Fujitaetal351115(32.8%)236(67.2%)61n/sn/sn/sn/sn/s188(53.6%)163(46.4%)n/s Haraetal17765(36.7%)112(63.3%)56.0n/s60(33.9%)102(57.6%)15(8.5%)32(18.1%)36(20.3%)109(61.6%)n/s Ishibeetal8431(36.9%)53(63.1%)62n/sn/sn/sn/s8(9.5%)25(29.8%)39(46.4%)12(14.3%) Kanemitsuetal1191419(35.2%)772(64.9%)5726(2.2%)348(29.2%)731(61.4%)86(7.2%)244(20.5%)351(29.5%)596(50.0%)n/s Ishidaetal4716(34%)31(66%)62n/sn/sn/sn/s11(23.4%)13(27.7%)23(48.9%)n/s Kagawaetal508(16%)42(84%)62n/sn/sn/sn/s6(12%)11(22.0%)28(56.0%)5(10.0%) Masakietal5516(29.1%)39(70.9%)n/sn/sn/s46(83.6%)n/sn/sn/sn/sn/s Matsuokaetal5116(31.4%)35(68.6%)63n/sn/s46(90.2%)5(9.8%)n/sn/sn/sn/s Miyakeetal258(32%)17(68%)672(8.0%)10(40.0%)8(32.0%)1(4.0%)10(40.0%)3(12.0%)3(12.0%)5(20.0%) Minetal15175(49.7%)76(50.3%)52.6n/sn/sn/sn/sn/sn/sn/sn/s Satoetal6724(35.8%)43(64.2%)63n/sn/s56(83.6%)11(16.4%)n/sn/sn/sn/s Satoetal14951(34.2%)98(65.8%)n/sn/s13(8.7%)125(83.9%)11(7.4%)n/sn/sn/sn/s Shimoyamaetal66n/sn/sn/sn/sn/sn/sn/sn/sn/s Yokoyamaetal13140(30.5%)91(69.5%)n/sn/sn/sn/sn/sn/sn/sn/sn/s Komorietal88n/sn/sn/sn/sn/sn/sn/sn/sn/s Masakietal4112(29.3%)29(70.7%)n/sn/sn/sn/sn/sn/sn/sn/sn/s Wuetal9650(52.1%)46(47.9%)65n/sn/sn/sn/sn/sn/sn/sn/s Uenoetal244n/sn/sn/sn/sn/sn/sn/sn/sn/sn/sn/s Steupetal605n/sn/sn/sn/sn/sn/sn/sn/sn/sn/sn/s Morietal15762(39.5%)95(60.5%)n/sn/sn/sn/sn/sn/sn/sn/sn/s Tanetal1046340(32.5%)706(67.5%)58.6189(18.1%)301(28.8%)516(49.3%)32(3.1%)n/sn/sn/sn/s Nagasakietal37127(7.3%)46(12.4%)61n/sn/s66(17.8%)n/sn/sn/sn/sn/s Yamaokaetal15035(23.3%)115(76.7%)61.56(4.0%)33(22.0%)88(58.7%)23(15.3%)n/s30(20.0%)79(52.6%)17(11.3%) Numataetal22965(28.4%)164(71.6%)61n/s41(17.9%)160(69.9%)28(12.2%)30(13.1%)75(32.8%)119(52%)5(2.2%) Yamaguchietal17339(22.5%)134(77.5%)n/sn/sn/sn/sn/s23(13.3%)41(23.7%)93(53.4%)16(9.2%) Yuetal9642(43.4%)54(56.3%)60n/sn/sn/sn/sn/sn/sn/sn/s Kobayashietal784277(35.3%)507(64.7%)n/s37(4.7%)207(26.4%)497(63.4%)43(5.5%)179(22.8%)224(28.6%)381(48.6%)n/s Yanoetal109n/sn/sn/sn/sn/sn/sn/sn/sn/sn/sn/s Kinugasaetal994349(35.1%)645(64.9%)n/s142(14.3%)260(26.2%)658(66.2%)384(38.6%)n/sn/sn/sn/s Uenoetal23791(38.4%)146(61.6%)58224(94.5%)13(5.5%)n/sn/sn/sn/s Hidaetal198n/sn/sn/s8(4.0%)38(19.2%)128(64.6%)24(12.1%)n/sn/sn/sn/s
Table3CharacteristicsofstudiesaccordingtothetypeofLLNDsurgeryandneoadjuvanttreatment AuthorsNeoadjuvant treatmentSurgicalapproach, nAreasofLLNDUnilateral/ BilateralMetastaticlaterallymphnodes, n(%)R0resection, n(%) FujitaetalNoOpenIC?II?IE?O?MSMixed26(7.4%)n/s HaraetalNon/sII?MS?O±Aobifurcation±IC±EIMixed32(18.1%)n/s IshibeetalNon/sIC?II?IE?OMixed16(19%)n/s KanemitsuetalSelectedpatientsn/sAobifurcation?IC?II?IE?0Mixed92(7.7%)n/s IshidaetalNon/sO?IIMixed11(23.4%)n/s KagawaetalSelectedpatientsRobotic-assistedIC?II?OMixed10(20%)n/s MasakietalYesOpenIC?II?OMixed11(20%)50(90.9%) MatsuokaetalYesn/sMixed15(29.4%)n/s MiyakeetalSelectedpatientsn/sIC?II?IE?OBilateral4(16%)n/s MinetalSelectedpatientsn/sAo?I?OMixed36(23.8%)133(88.1%) SatoetalYesn/sII?IE?OMixed6(9%)n/s SatoetalNon/sMixed64(43%)n/s Shimoyama etalNon/sAo?II?IE?ICMixed20(30.3%)n/s YokoyamaetalNon/sIC?II?IE?OMixed26(19.8%)n/s KomorietalNon/sIC?II?IE?OMixed14(15.9%)n/s MasakietalNon/sIC?II?IE?OBilateral10(24.4%)n/s WuetalNon/sMixed14(14.6%)n/s UenoetalNon/sinternal pudendal?IC?II?IE?O?MSMixed41(16.8%)n/s SteupetalNon/sIC?II?OMixed83(13.7%)n/s MorietalNoOpenII?EI?OMixed40(25.5%)n/s TanetalNon/sn/sMixed113(10.8%)n/s NagasakietalSelectedpatientsn/sII?EI?O?CIMixed73(19.7%)68(18.3%) YamaokaetalSelectedpatientsOpen:27 Robot:115 Laparoscopy:8
CI,II,OMixed34(22.7%)n/s NumataetalNoOpen:199 Robot:28 Laparoscopy:2
CI,II,OBilateral32(14%)229(100%) YamaguchietalNoOpen:88,Robot: 85CI,II,OMixed32(18.5%)n/s YuetalNon/sCI,II,MS,O,EIn/s14(14.6%)n/s Kobayashietaln/sn/sn/sn/s117(14.9%)n/s Yanoetaln/sn/sn/sn/s21(53.8%)103(94.5%)
Our meta-analysis is the first to examine the prevalence of metastatic lateral lymph nodes, which seems to be an essential prerequisite before considering any treatment.
Indeed, recent literature [40–42] directly questions the oncological and functional results of LLND without even first investigating whether it is necessary.
Advantages of the study
The strengths of our systematic review and meta-analysis are as follows: 1) the inclusion of a large number of studies reporting the prevalence of metastatic lateral lymph nodes based on histopathological analysis and to clarify, for the first time to our knowledge, its subsequent effects in patients operated on for rectal cancer; and 2) the high- lighting of the necessity of systematic treatment of lateral lymph nodes due to the high prevalence (17.3%) of LLN metastasis. Indeed, despite the heterogeneity of the studies, which could have impacted the aim of our work, we were able to make some sound calculations due to a specific statistical analysis methodology.
Limitations of the study
The limitations of the present study are as follows: 1) the high heterogeneity of the calculated pooled prevalence of metastatic lateral lymph nodes, resulting from the quality and heterogeneity of the included publications; and 2) the final analysis included 31 papers, most of which were from Japan and were retrospective studies. Therefore, some patients might have overlapped because these papers were published from some limited leading hospitals. Moreover, it is worth noting that by focussing on patients who have benefited from LLND, a surgical procedure that is most common in Asian countries, selection has been carried out.
As a result, it is expected that the selected studies tend to oversample patients with indications for LLND, with these patients being more likely to have advanced disease. Thus, a bias could have been introduced. The percentage of 17.3% of metastatic LLNs could have been overestimated.
This element can explain the counter-intuitive (but non- significant) results of a higher prevalence of metastasis in the prophylactic LLND group (17.3%)versusthe curative group (15.9%).
Conclusion
In conclusion, this systematic review and meta-analysis of Asian studies indicates that the prevalence of metastatic lateral lymph nodes in patients with low rectal cancer who underwent surgery is 17.3%. This prevalence is of clinical importance, as it may result in cancer recurrence and calls Table3continued AuthorsNeoadjuvant treatmentSurgicalapproach, nAreasofLLNDUnilateral/ BilateralMetastaticlaterallymphnodes, n(%)R0resection, n(%) KinugasaetalNon/sn/sMixed59(13.1)n/s UenoetalNon/sCI,IE,II,middlerectalMixed41(17.3%)237(100%) HidaetalNon/sCI,O,II,middlerectaln/s22(11.1%)n/s Commoniliac(IC),internaliliacnode(II),externaliliacnode(EI),obturatornode(O),middlesacralnode(MS),aorta(Ao)
for the systematic treatment of these lymph node areas.
Future randomized controlled trials should determine which therapeutic strategy, whether neoadjuvant radiochemotherapy versus systematic or imaging-guided lateral lymph node dissection, offers the best improvement in overall and recurrence-free survival.
Author contributions JM conceived and designed the study. JM and NC acquired the data. CC analysed the data. NC, JM, CC, AB, NCB and FR interpreted the data. NC, JM, CC, AB, JRY, NCB and FR contributed to the writing of the manuscript and to its critical revision.
NC, JM, CC, AB, JRY, NCB and FR approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of interest.
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References
1. Funahashi K, Koike J, Shimada M, Okamoto K, Goto T, Ter- amoto T (2006) A preliminary study of the draining lymph node basin in advanced lower rectal cancer using a radioactive tracer.
Dis Colon Rectum 49(10 Suppl):S53-58
2. Manfredi S, Benhamiche AM, Meny B, Cheynel N, Rat P, Faivre J (2001) Population-based study of factors influencing occurrence and prognosis of local recurrence after surgery for rectal cancer.
Br J Surg 88(9):1221–1227
3. van de Velde CJ, Boelens PG, Borras JM et al (2014) EURECCA colorectal: multidisciplinary management: European consensus conference colon and rectum. Eur J Cancer 50(1):1-e1
4. Watanabe T, Muro K, Ajioka Y et al (2018) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol 23(1):1–34 Study
Random effects model Prediction interval
Heterogeneity: I2 = 89%, 2 = 0.2779, p < 0.01 Hida, 1997
Mori, 1998 Steup, 2002 Shimoyama, 2003 Ueno, 2005 Hara, 2007 Matsuoka, 2007 Ueno, 2007 Wu, 2007 Yano, 2007 Masaki, 2008 Kobayashi, 2009 Min, 2009 Masaki, 2010 Tan, 2010 Sato, 2011a Sato, 2011b Yu, 2011 Fujita, 2012 Ishida, 2012 Kinugasa, 2013 Komori, 2013 Yokoyama, 2014 Kagawa, 2015 Ishibe, 2016 Yamaguchi, 2016 Kanemitsu, 2017 Miyake, 2017 Nagasaki, 2017 Numata, 2017 Yamaoka, 2017
Events
22 40 83 20 41 32 15 41 14 21 10 117 6 11 113 6 64 14 26 11 59 14 26 10 16 32 92 4 73 32 34
Total
7599 198 157 605 66 237 177 51 244 96 39 41 784 151 55 1046 67 149 96 351 47 450 88 131 50 84 173 1191 25 371 229 150
0.1 0.2 0.3 0.4 0.5 0.6
Proportion
0.173 0.111 0.255 0.137 0.303 0.173 0.181 0.294 0.168 0.146 0.538 0.244 0.149 0.040 0.200 0.108 0.090 0.430 0.146 0.074 0.234 0.131 0.159 0.198 0.200 0.190 0.185 0.077 0.160 0.197 0.140 0.227
95% CI
[0.146; 0.204]
[0.065; 0.386]
[0.071; 0.163]
[0.189; 0.330]
[0.111; 0.167]
[0.196; 0.429]
[0.127; 0.227]
[0.127; 0.246]
[0.175; 0.438]
[0.123; 0.221]
[0.082; 0.233]
[0.372; 0.699]
[0.124; 0.403]
[0.125; 0.176]
[0.015; 0.084]
[0.104; 0.330]
[0.090; 0.128]
[0.034; 0.185]
[0.349; 0.513]
[0.082; 0.233]
[0.049; 0.107]
[0.123; 0.380]
[0.101; 0.166]
[0.090; 0.252]
[0.134; 0.277]
[0.100; 0.337]
[0.113; 0.291]
[0.130; 0.251]
[0.063; 0.094]
[0.045; 0.361]
[0.158; 0.241]
[0.098; 0.192]
[0.162; 0.302]
Weight
100.0%
3.3%
3.5%
3.8%
3.1%
3.6%
3.5%
3.0%
3.6%
3.0%
2.9%
2.7%
3.8%
2.4%
2.8%
3.8%
2.4%
3.6%
3.0%
3.4%
2.8%
3.7%
3.0%
3.4%
2.7%
3.1%
3.5%
3.8%
1.9%
3.7%
3.5%
3.5%
Fig. 2 Meta-analysis of the prevalence of metastatic lateral lymph nodes
5. Fujita S, Akasu T, Mizusawa J et al (2012) Postoperative mor- bidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): results from a multicentre, randomised controlled, non-inferiority trial. Lancet Oncol 13(6):616–621
6. Masaki T, Matsuoka H, Kobayashi T et al (2010) Quality assurance of pelvic autonomic nerve-preserving surgery for advanced lower rectal cancer–preliminary results of a random- ized controlled trial. Langenbecks Arch Surg 395(6):607–613 7. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials.
Control Clin Trials 7(3):177–188
8. Viechtbauer W, Lopez-Lopez JA, Sanchez-Meca J, Marin-Mar- tinez F (2015) A comparison of procedures to test for moderators in mixed-effects meta-regression models. Psychol Methods 20(3):360–374
9. Hara M, Hirai T, Nakanishi H et al (2007) Isolated tumor cell in lateral lymph node has no influences on the prognosis of rectal cancer patients. Int J Colorectal Dis 22(8):911–917
10. Ishibe A, Ota M, Watanabe J et al (2016) Prediction of lateral pelvic lymph-node metastasis in low rectal cancer by magnetic resonance imaging. World J Surg 40(4):995–1001
11. Kanemitsu Y, Komori K, Shida D et al (2017) Potential impact of lateral lymph node dissection (LLND) for low rectal cancer on prognoses and local control: a comparison of 2 high-volume centers in Japan that employ different policies concerning LLND.
Surgery 162(2):303–314
12. Ishida H, Hatano S, Ishiguro T, Kumamoto K, Ishibashi K, Haga N (2012) Prediction of lateral lymph node metastasis in lower rectal cancer: analysis of paraffin-embedded sections. Jpn J Clin Oncol 42(6):485–490
13. Kagawa H, Kinugasa Y, Shiomi A et al (2015) Robotic-assisted lateral lymph node dissection for lower rectal cancer: short-term outcomes in 50 consecutive patients. Surg Endosc 29(4):995–1000
14. Matsuoka H, Nakamura A, Masaki T et al (2007) Optimal diagnostic criteria for lateral pelvic lymph node metastasis in rectal carcinoma. Anticancer Res 27(5B):3529–3533
15. Miyake Y, Mizushima T, Hata T et al (2017) Inspection of perirectal lymph nodes by one-step nucleic acid amplification predicts lateral lymph node metastasis in advanced rectal cancer.
Ann Surg Oncol 24(13):3850–3856
16. Min BS, Kim JS, Kim NK et al (2009) Extended lymph node dissection for rectal cancer with radiologically diagnosed extramesenteric lymph node metastasis. Ann Surg Oncol 16(12):3271–3278
17. Sato T, Ozawa H, Hatate K et al (2011) A Phase II trial of neoadjuvant preoperative chemoradiotherapy with S-1 plus irinotecan and radiation in patients with locally advanced rectal cancer: clinical feasibility and response rate. Int J Radiat Oncol Biol Phys 79(3):677–683
18. Sato H, Maeda K, Maruta M (2011) Prognostic significance of lateral lymph node dissection in node positive low rectal carci- noma. Int J Colorectal Dis 26(7):881–889
19. Shimoyama M, Yamazaki T, Suda T, Hatakeyama K (2003) Prognostic significance of lateral lymph node micrometastases in lower rectal cancer: an immunohistochemical study with CAM5.2. Dis Colon Rectum 46(3):333–339
20. Yokoyama S, Takifuji K, Hotta T et al (2014) Survival benefit of lateral lymph node dissection according to the region of involvement and the number of lateral lymph nodes involved.
Surg Today 44(6):1097–1103
21. Komori K, Kanemitsu Y, Kimura K et al (2013) Detailed strati- fication of TNM stage III rectal cancer based on the presence/
absence of extracapsular invasion of the metastatic lymph nodes.
Dis Colon Rectum 56(6):726–732
22. Masaki T, Takayama M, Matsuoka H et al (2008) Intraoperative radiotherapy for oncological and function-preserving surgery in patients with advanced lower rectal cancer. Langenbecks Arch Surg 393(2):173–180
23. Wu ZY, Wan J, Li JH et al (2007) Prognostic value of lateral lymph node metastasis for advanced low rectal cancer. World J Gastroenterol 13(45):6048–6052
24. Hida J, Yasutomi M, Fujimoto K, Maruyama T, Okuno K, Shindo K (1997) Does lateral lymph node dissection improve survival in rectal carcinoma? examination of node metastases by the clearing method. J Am Coll Surg 184(5):475–480
25. Ueno M, Oya M, Azekura K, Yamaguchi T, Muto T (2005) Incidence and prognostic significance of lateral lymph node metastasis in patients with advanced low rectal cancer. Br J Surg 92(6):756–763
26. Ueno H, Mochizuki H, Hashiguchi Y et al (2007) Potential prognostic benefit of lateral pelvic node dissection for rectal cancer located below the peritoneal reflection. Ann Surg 245(1):80–87
27. Steup WH, Hojo K, Moriya Y et al (1994) An analysis on the effect of blood transfusion on recurrence and survival in patients undergoing extended lymphadenectomy for colorectal cancer.
Hepatogastroenterology 41(3):253–259
28. Mori T, Takahashi K, Yasuno M (1998) Radical resection with autonomic nerve preservation and lymph node dissection tech- niques in lower rectal cancer surgery and its results: the impact of lateral lymph node dissection. Langenbecks Arch Surg 383(6):409–415
29. Tan KY, Yamamoto S, Fujita S, Akasu T, Moriya Y (2010) Improving prediction of lateral node spread in low rectal cancers–
multivariate analysis of clinicopathological factors in 1046 cases.
Langenbecks Arch Surg 395(5):545–549
30. Nagasaki T, Akiyoshi T, Fujimoto Y et al (2017) Preoperative chemoradiotherapy might improve the prognosis of patients with locally advanced low rectal cancer and lateral pelvic lymph node metastases. World J Surg 41(3):876–883
31. Yamaoka Y, Kinugasa Y, Shiomi A et al (2017) Preoperative chemoradiotherapy changes the size criterion for predicting lat- eral lymph node metastasis in lower rectal cancer. Int J Colorectal Dis 32(11):1631–1637
32. Numata M, Yamaguchi T, Kinugasa Y et al (2017) Index of estimated benefit from lateral lymph node dissection for middle and lower rectal cancer. Anticancer Res 37(5):2549–2555 33. Yamaguchi T, Kinugasa Y, Shiomi A, Tomioka H, Kagawa H,
Yamakawa Y (2016) Robotic-assisted vs. conventional laparo- scopic surgery for rectal cancer: short-term outcomes at a single center. Surg Today 46(8):957–962
34. Yu YY, Wang C, Xu D, Shen XG, Ding SQ, Zhou ZG (2011) Mesorectal and lateral node metastasis and micrometastasis in lower rectal cancer. Hepatogastroenterology 58(107–108):745–748
35. Kobayashi H, Mochizuki H, Kato T et al (2009) Outcomes of surgery alone for lower rectal cancer with and without pelvic sidewall dissection. Dis Colon Rectum 52(4):567–576
36. Yano H, Saito Y, Takeshita E, Miyake O, Ishizuka N (2007) Prediction of lateral pelvic node involvement in low rectal cancer by conventional computed tomography. Br J Surg 94(8):1014–1019
37. Kinugasa T, Akagi Y, Ochi T et al (2013) Lateral lymph-node dissection for rectal cancer: meta-analysis of all 944 cases undergoing surgery during 1975–2004. Anticancer Res 33(7):2921–2927
38. Yamaguchi T, Kinugasa Y, Shiomi A, Tomioka H, Kagawa H (2016) Robotic-assisted laparoscopic versus open lateral lymph node dissection for advanced lower rectal cancer. Surg Endosc 30(2):721–728
39. Steup WH, Moriya Y, van de Velde CJ (2002) Patterns of lym- phatic spread in rectal cancer. a topographical analysis on lymph node metastases. Eur J Cancer. 38(7):911–918
40. Du R, Zhou J, Li D, Zhang Q, Liu J, Ma C, et al. (2020) Post- operative morbidity and mortality after mesorectal excision with laparoscopic versus conventional open lateral lymph node dis- section for advanced rectal cancer: a meta-analysis. Asian J Surg [Internet]. 11 aouˆt 2020; Disponible sur: http://www.sciencedir ect.com/science/article/pii/S1015958420301950
41. Yang X, Yang S, Hu T, Gu C, Wei M, Deng X et al (2020) What is the role of lateral lymph node dissection in rectal cancer patients with clinically suspected lateral lymph node metastasis
after preoperative chemoradiotherapy? a meta-analysis and sys- tematic review. Cancer Med 9(13):4477–4489
42. Gao X, Wang C, Yu Y, Yang L, Zhou Z (2020) Lateral lymph node dissection reduces local recurrence of locally advanced lower rectal cancer in the absence of preoperative neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. Dis- ponible sur:https://europepmc.org/article/ppr/ppr216100 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
